Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission.
Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission.
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慢性粒细胞白血病的免疫效应恢复和无治疗缓解。
DOI：
10.3389/fimmu.2017.00469
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发表时间：
2017
影响因子：
7.3
通讯作者：
Yong ASM
中科院分区：
文献类型：
--
作者：
Hughes A;Yong ASM
慢性粒细胞白血病（CML）是一种血液学癌症，其特征在于染色体9和22 [t（9;22）]之间的相互染色体易位，产生Bcr-Abl癌基因。酪氨酸激酶抑制剂（TKI）代表了CML患者的标准治疗，并发挥双重作用模式：直接抑制癌激酶和恢复效应介导的免疫监视，在TKI治疗前，CML患者在诊断时出现功能障碍。TKI（如伊马替尼）和更强效的第二代尼洛替尼和达沙替尼在CML患者中诱导了较高的深度分子学缓解率（DMR，BCR-ABL 1 ≤ 0.01%）。因此，CML治疗的最新目标是诱导持久的DMR，作为成功的无治疗缓解（TFR）的前奏，这发生在大约一半停止TKI治疗的CML患者中。这些患者没有明显复发归因于CML的免疫控制。在这篇综述中，我们讨论了成功的TFR的免疫学时间轴，重点是TKI治疗期间CML的免疫学;免疫抑制的初始阶段，限制新诊断的CML患者的抗肿瘤免疫效应反应，与未成熟骨髓源性抑制细胞和调节性T细胞的扩增以及免疫检查点信号通路（包括程序性死亡-1/程序性死亡配体-1）的异常表达有关。TKI治疗的开始与CML患者的免疫系统重新激活和效应介导的[自然杀伤（NK）细胞和T细胞]免疫监视的恢复相关，尽管TKI治疗获得的分子应答水平不同，频率也不同。DMR与接受TKI治疗的CML患者的免疫恢复最大程度恢复相关。目前的数据表明，免疫系统的效应臂和抑制臂之间的净平衡，至少涉及成熟的细胞毒性CD 56 dim NK细胞，可能在介导TFR成功方面很重要。然而，CML的一个主要目标仍然是确定最有效的靶向途径，以最大限度地提高有利的免疫应答并促进TFR成功。
Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating TFR success. However, a major goal remains in CML to identify the most effective pathways to target to maximize an advantageous immune response and promote TFR success.